hENT1 as a Predictive Biomarker in PDAC—Letter
Authors: Lenka N.C. Boyd, Mahsoem Ali, Jisce R. Puik, Laura L. Meijer, Tessa Y.S. Le Large, Hanneke W.M. van Laarhoven, Elisa Giovannetti, Geert Kazemier
Journal: Clinical Cancer Research (2023)

The clinical management of pancreatic ductal adenocarcinoma (PDAC) is limited by the lack of biomarkers that indicate which treatment will benefit an individual patient. The study of Perera and colleagues identified human equilibrative nucleoside transporter-1 (hENT1) mRNA expression as a predictive biomarker in patients suffering from advanced PDAC (1). Remarkably, hENT1high expression was predictive of response to gemcitabine/nab-paclitaxel. hENT1 levels were not predictive in patients treated with (modified) FOLFIRINOX, which currently is the preferred regimen for advanced PDAC. These results can hopefully pave the way for personalized treatment strategies. However, some key points of the study should be further discussed.Expression of hENT1 was evaluated by RNA sequencing after laser-capture microdissection (LCM) of tumor tissue. These techniques require thorough laboratory expertise and are not easy to implement in the clinic. To promote clinical implementation and overcome the lack of robust antibodies for hENT1 protein detection, the proposed validation study in the PASS-01 trial should compare these techniques with multimodal IHC and PCR techniques (2), and possibly mass spectrometry–based proteomics to examine expression and posttranscriptional modificationsRNA sequencing provides expression levels for all genes, thus revealing many potential targets and underlying pathways. However, the authors only evaluated hENT1 levels, not utilizing the full extent of the valuable data. Conversely, LCM relies on removing stromal microenvironment, which plays an integral role in chemoresistance and is correlated to disease progression (3). Thus, it would be of value to explore the expression of compartment-specific predictive markers in LCM-stroma samples. In addition, samples were taken from primary and metastatic tumors (in a cohort including locally advanced and metastatic patients). The next step for implementation would be to evaluate these findings in biopsies from a neoadjuvant-treated cohort and correlate to clinicopathologic response.In a group of matched progression biopsies, hENT1 expression changed during treatment. This is another important finding, suggesting that hENT1 levels should be monitored during treatment. In addition, the change from hENT1low to hENT1high in FOLFIRINOX-treated patients is in agreement with preclinical studies showing increased hENT1 expression, associated with depletion of intracellular nucleotide pools after exposure to the thymidylate synthase (TS) inhibitor 5-fluoruracil (4). Further studies could evaluate whether modulation of hENT1 by pretreatment with FOLFIRINOX or TS-inhibitors may improve the therapeutic benefit of gemcitabine/nab-paclitaxel.To conclude, we congratulate the authors on their thorough research on the predictive role of hENT1 for PDAC, and believe that these results lay the groundworks for future research aimed to understand the link between hENT1 and patient outcomes.See the Response, p. 2945H.W. van Laarhoven reports personal fees from AstraZeneca, Daiichy, Dragonfly, MSD, Astellas, Lilly; grants and personal fees from BMS, Servier; grants from Incyte, Merck, Roche; and personal fees from Novartis outside the submitted work; in addition, H.W. van Laarhoven has a patent for US20210145964A1 pending to Bijlsma/van Laarhoven. No disclosures were reported by the other authors.This article was funded by the Dutch Cancer Society (to G. Kazemier and E. Giovannetti), Bennink Foundation (the Netherlands; to G. Kazemier, L.N.C. Boyd, M. Ali, J.R. Puik, and E. Giovannetti) and Italian Association for Cancer Research (Italy; to E. Giovannetti).